Using dynamic combinatorial selection methods to identify chemical modifications of protein function

使用动态组合选择方法来识别蛋白质功能的化学修饰

• 批准号: 2739406
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2739406
• 关键词: Using; dynamic; combinatorial; selection; methods

Intrinsically disordered regions (IDRs), are ubiquitous stretches of protein that do not adopt a stable structure, are a major class of protein structure found in all living organisms, and, are predicted to be present in around a third of eukaryotic proteins. Crucially, IDRs are important and overrepresented in key signalling and disease pathways, spanning cancer to disorders of protein aggregation.This PhD studentship will exploit chemical biology approaches to understand and manipulate the aggregation behaviour of a-synuclein - an intrinsically disordered protein which plays a key role in the neurodegenerative condition: Parkinson's disease. We will apply a state of the art combination of peptide and protein chemistry, fragment based ligand discovery methods and advanced biophysical techniques and structural methods to identify modifications to the sequence of a-synuclein and systematically map the consequences for its aggregation behaviour in vitro and in cells. The results will establish a platform to identify modulators of IDRs/IDPs and open the door to new methods to delineate aggregation mechanisms a basic question of critical importance and tools to drive drug-discovery.

内含子无序区（IDR）是普遍存在的不采用稳定结构的蛋白质片段，是在所有生物体中发现的主要蛋白质结构类别，并且预计存在于约三分之一的真核蛋白质中。最重要的是，IDR在关键信号传导和疾病途径中非常重要，并且在癌症和蛋白质聚集障碍中占主导地位。这个博士生项目将利用化学生物学方法来理解和操纵a-突触核蛋白的聚集行为-一种内在无序的蛋白质，在神经退行性疾病中起着关键作用：帕金森病。我们将应用肽和蛋白质化学、基于片段的配体发现方法和先进的生物物理技术和结构方法的最新组合来鉴定α-突触核蛋白序列的修饰，并系统地绘制其体外和细胞中聚集行为的后果。研究结果将建立一个平台，以确定药物依赖反应/国内流离失所者的调节剂，并为描述聚集机制的新方法打开大门，这是一个至关重要的基本问题，也是推动药物发现的工具。